tbuckley/cabot-search huggingface dataset:
Impact of <i>STK11</i> copy loss on clinical outcomes to PD-(L)1 blockade in non–small cell lung cancer.
Authors: Catherine Gutierrez, Biagio Ricciuti, Joao Victor Machado Alessi, Federica Pecci, Adriana Paula de Castro Barrichello, Victor R. Vaz, Lynette M. Sholl, Mark M. Awad
Journal: Journal of Clinical Oncology (2022)

9059 Background: STK11 is among the most commonly altered genes in non-squamous lung cancers. While STK11 mutation is associated with diminished efficacy of immune checkpoint inhibition (ICI), particularly in KRAS mutated tumors, it is not known whether STK11 copy deletion influences outcomes to ICI. Methods: Patients with advanced non-squamous non-small cell lung cancer (NSCLC) treated with ICI whose tumors underwent genomic profiling were included. Clinical outcomes to ICI were analyzed according to KRAS mutation and STK11 deletions. STK11 copy number variations (CNVs) were determined using an internal informatic pipeline. Kaplan-Meier methodology was used to estimate event-time distributions. Results: Of 559 patients with non-squamous NSCLCs (Nsq-NSCLC), 40.4% (N = 226) had a KRAS mutation ( KRAS mut ), 18.4% (N = 103) had an oncogenic STK11 mutation ( STK11 mut ), and 22.5% had either single (N = 123), or bi-allelic (N = 3) deletion ( STK11 del ). Given that 32.5% of STK11 del cases had a concurrent oncogenic STK11 mutation in our cohort, to isolate the impact of STK11 del on ICI outcomes we excluded samples with STK11 mut from this analysis. In all comers with NSCLC, STK11 del had no impact on objective response rate (22.2% versus 23.8%, P = 0.8), progression-free (PFS, HR 0.90, P = 0.30), and overall survival (OS, HR 0.96, P = 0.79) to ICI. When we examined the impact of STK11 del on clinical outcomes to PD-(L)1 blockade among KRAS mut cases we found that STK11 del was associated with a numerically lower ORR (13.3% versus 30.0%, P = 0.12), and a significantly shorter PFS (HR 0.57, P = 0.018) compared to cases without STK11 del . No difference in OS were observed between these groups (HR 0.77, P = 0.39). Among KRAS wt NSCLCs, STK11 del cases had a similar ORR (22.6% versus 22.9%, P = 0.99), PFS (HR 0.92, P = 0.63), and OS (HR 1.18, P = 0.32) to PD-(L)1 inhibition compared to cases without STK11 del . Among KRAS mut but not KRAS wt NSCLCs, cases with STK11 del had significantly lower PD-L1 expression compared to those without STK11 deletions (27.5% versus 70%, P = 0.01). Conclusions: STK11 deletion is associated with low response rate and short progression-free survival among KRAS mutant NSCLCs. Future analyses will incorporate additional cases to increase sample size and immunopathologic findings to assess impact of mono and bi-allelic deletion on protein expression.
Two checkpoint inhibitor combinations in patients with cutaneous melanoma: A systematic review of clinical trials.
Authors: Wajeeha Aiman, Mati Ullah Dad Ullah, Mukarram Jamat Jamat Ali, Iman Waheed Khan, Mina Choudhry, Hafsa Chaudry, Aqsa Anwar, Sreekant Avula, Faiz Anwer, Muhammad Ashar Ali
Journal: Journal of Clinical Oncology (2022)

e21530 Background: Melanoma is a cancer of melanocytes and has the potential to metastasize to distant organs. Immune checkpoint inhibitors (ICI) enhance the immune response against cancer cells. Programmed cell death protein-1 (PD-1), PD-ligand-1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and lymphocyte-activation gene (LAG-3) are the common targets of ICI. Blocking two pathways can have an additive/synergistic effect. This systematic review will assess the efficacy of two ICI combinations in cutaneous melanoma. Methods: A search was performed on PubMed, Embase, and clinicaltrials.gov. We used the following mesh and Emtree terms, “Melanoma” AND “Immune checkpoint inhibitors,” from the inception of literature till 01/15/2022. We screened 11,287 articles and included 4 randomized clinical trials (N = 1,948) and 6 single-arm clinical trials (N = 438) in this review. We excluded preclinical trials, case reports, case series, review articles, observational studies, meta-analysis, and irrelevant clinical trials. Results: In 10 clinical studies (N = 2,386), two ICI combinations were assessed in adult patients with melanoma. Nivolumab (nivo) + ipilimumab (ipi), relatlimab (rela) + nivo, pembrolizumab (pemb) + ipi, lag525 + spartalizumab (spa), fianlimab (fian) + cemiplimab (cem) and single drug/placebo were used to treat 560, 365, 223, 42, 48, and 1,148 patients, respectively. 2,119, 70, and 197 patients had advanced untreated, PD-1/L1 refractory, and resectable stage III/IV melanoma. The response rates (RR) and survival rates are given in table. Conclusions: Two ICI combinations of nivo, ipi, and rela were more effective than monotherapy in patients with untreated advanced melanoma. In early phase trials, combinations of ipi, nivo, pemb, lag525, spa, fian, and cem were effective in advanced melanoma. Nivo, ipi, and rela were effective in patients with resectable melanoma. Pemb+ipi was effective in patients with PD-1/L1 refractory melanoma. More randomized double-blinded clinical trials are needed to confirm these results.[Table: see text]
The Effect of Sacral Neuromodulation (SNM) on Nocturia in patients with Overactive Bladder Syndrome (OAB)
Authors: P. Daemi Attaran, J.M.W. Janssen, G. Van Koeveringe, D. Vrijens, J. Heesakkers, M. Saar, M.S. Rahnama'i
Journal: European Urology (2022)
A mitochondrial unfolded protein response inhibitor suppresses prostate cancer growth in mice via HSP60
Authors: Rahul Kumar, Ajay K. Chaudhary, Jordan Woytash, Joseph R. Inigo, Abhiram A. Gokhale, Wiam Bshara, Kristopher Attwood, Jianmin Wang, Joseph A. Spernyak, Eva Rath, Neelu Yadav, Dirk Haller, David W. Goodrich, Dean G. Tang, Dhyan Chandra
Journal: Journal of Clinical Investigation (2022)

Mitochondrial proteostasis, regulated by the mitochondrial unfolded protein response (UPRmt), is crucial for maintenance of cellular functions and survival. Elevated oxidative and proteotoxic stress in mitochondria must be attenuated by the activation of a ubiquitous UPRmt to promote prostate cancer (PCa) growth. Here we show that the 2 key components of the UPRmt, heat shock protein 60 (HSP60, a mitochondrial chaperonin) and caseinolytic protease P (ClpP, a mitochondrial protease), were required for the development of advanced PCa. HSP60 regulated ClpP expression via c-Myc and physically interacted with ClpP to restore mitochondrial functions that promote cancer cell survival. HSP60 maintained the ATP-producing functions of mitochondria, which activated the β-catenin pathway and led to the upregulation of c-Myc. We identified a UPRmt inhibitor that blocked HSP60's interaction with ClpP and abrogated survival signaling without altering HSP60's chaperonin function. Disruption of HSP60-ClpP interaction with the UPRmt inhibitor triggered metabolic stress and impeded PCa-promoting signaling. Treatment with the UPRmt inhibitor or genetic ablation of Hsp60 inhibited PCa growth and progression. Together, our findings demonstrate that the HSP60-ClpP-mediated UPRmt is essential for prostate tumorigenesis and the HSP60-ClpP interaction represents a therapeutic vulnerability in PCa.
AP4 suppresses DNA damage, chromosomal instability and senescence via inducing MDC1/Mediator of DNA damage Checkpoint 1 and repressing MIR22HG/miR-22-3p
Authors: Jinjiang Chou, Markus Kaller, Stephanie Jaeckel, Matjaz Rokavec, Heiko Hermeking
Journal: Molecular Cancer (2022)

AP4 (TFAP4) encodes a basic helix-loop-helix leucine zipper (bHLH-LZ) transcription factor and is a direct target gene of the oncogenic transcription factor c-MYC. Here, we set out to determine the relevance of AP4 in human colorectal cancer (CRC) cells.A CRISPR/Cas9 approach was employed to generate AP4-deficient CRC cell lines with inducible expression of c-MYC. Colony formation, β-gal staining, immunofluorescence, comet and homologous recombination (HR) assays and RNA-Seq analysis were used to determine the effects of AP4 inactivation. qPCR and qChIP analyses was performed to validate differentially expressed AP4 targets. Expression data from CRC cohorts was subjected to bioinformatics analyses. Immunohistochemistry was used to evaluate AP4 targets in vivo. Ap4-deficient APCmin/+ mice were analyzed to determine conservation. Immunofluorescence, chromosome and micronuclei enumeration, MTT and colony formation assays were used to determine the effects of AP4 inactivation and target gene regulation on chromosomal instability (CIN) and drug sensitivity.Inactivation of AP4 in CRC cell lines resulted in increased spontaneous and c-MYC-induced DNA damage, chromosomal instability (CIN) and cellular senescence. AP4-deficient cells displayed increased expression of the long non-coding RNA MIR22HG, which encodes miR-22-3p and was directly repressed by AP4. Furthermore, Mediator of DNA damage Checkpoint 1 (MDC1), a central component of the DNA damage response and a known target of miR-22-3p, displayed decreased expression in AP4-deficient cells. Accordingly, MDC1 was directly induced by AP4 and indirectly by AP4-mediated repression of miR-22-3p. Adenomas and organoids from Ap4-deficient APCmin/+ mice displayed conservation of these regulations. Inhibition of miR-22-3p or ectopic MDC1 expression reversed the increased senescence, DNA damage, CIN and defective HR observed in AP4-deficient CRC cells. AP4-deficiency also sensitized CRC cells to 5-FU treatment, whereas ectopic AP4 conferred resistance to 5-FU in a miR-22-3p and MDC1-dependent manner.In summary, AP4, miR-22-3p and MDC1 form a conserved and coherent, regulatory feed-forward loop to promote DNA repair, which suppresses DNA damage, senescence and CIN, and contributes to 5-FU resistance. These findings explain how elevated AP4 expression contributes to development and chemo-resistance of colorectal cancer after c-MYC activation.
RARE-32. Phase 0 and feasibility single-institution clinical trial of intravenous tocilizumab for adamantinomatous craniopharyngioma
Authors: Kathleen Dorris, Ashley Mettetal, Nathan Dahl, Molly Hemenway, Shelby Winzent-Oonk, Eric Prince, Trinka Vijmasi, Jennifer McWilliams, Kimberly Jordan, David Mirsky, Lindsey Hoffman, Todd Hankinson
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Adamantinomatous craniopharyngioma (ACP) is a devastating skull-base tumor believed to derive from epithelial remnants of the primordial craniopharyngeal duct (Rathke’s pouch), which gives rise to the anterior pituitary gland. ACP lacks medical antitumor therapies. Current standard therapy with surgery and radiation is associated with poor quality of life. Clinical and preclinical data indicate that IL-6 blockade may contribute to ACP tumor control. METHODS: Children aged 2–21 years with newly diagnosed or previously treated ACP with measurable disease are eligible for the Phase 0/feasibility single-institution clinical trial (NCT03970226) of intravenous (IV) tocilizumab at Children’s Hospital Colorado. The phase I stratum involves IV tocilizumab prior to a standard-of-care surgical resection. The feasibility portion of the trial involves IV tocilizumab every two weeks for up to 13 28-day cycles. Tocilizumab is administered at the established weight-based pediatric dosage of 8 mg/kg for patients who weigh ≥30kg or 12 mg/kg for patients who weigh &amp;lt;30kg. RESULTS: To date, three patients have been enrolled on the Phase 0 component of the trial. These patients demonstrated clinically relevant levels of tocilizumab (≥ 4µg/mL) in serum, cyst fluid, and/or tumor tissue, compared to undetectable levels in control samples. Two patients (1 male and 1 female; median age 10.5 years) have enrolled on the feasibility stratum; one patient had best response of minor response but met definition of progressive disease at cycle 11. One patient with extensive disease required dose reduction for myelosuppression. CONCLUSION: Systemic delivery of tocilizumab at the established pediatric dosage is promising for treatment of ACP based on preclinical work and its demonstrated penetration into cystic and solid portions of ACP tumors. The therapy to date has been well tolerated overall. Further study is planned through a CONNECT consortium international Phase II trial.
Quality of life in patients with de novo metastatic breast cancer undergoing locoregional surgery: A prospective observational study.
Authors: Ren Chongxi, Sun Jianna, Kong Lingjun, Mu Kun, Ren Reize
Journal: Journal of Clinical Oncology (2022)

e13044 Background: Breast cancer remains the most frequent type of cancer in women, with de novo metastatic breast cancer (dnMBC) accounting for approximately 10% of patients. Advances in diagnosis and treatment of breast cancer have led to an increase in cancer survival, resulting in quality of life (QoL) improvement. However, there are few reports on whether local treatment improves quality of life for de novo metastatic breast cancer (dnMBC). Aim: To evaluate QoL in dnMBC patients since randomization using scores from the FACT-B health survey. Settings and design: This study was designed as a prospective observational research project and was approved by the Ethics Committee of the Ethics Committee of Cangzhou Clinical College of Integrated Traditional Chinese and Western Medicine of Hebei Medical University (NO.20200212). Methods: Eighty-six patients with dnMBC were randomised to surgery of the primary tumor followed by systemic therapy (surgery group) or to primary systemic therapy without surgery (non-surgery group). QoL analyses covering the results at baseline, 6,12,18,24 and 30 months follow up of 81 (94%) patients, was assessed with the Functional Assessment of Chronic Illness Therapy General Questionnaire, including Breast Cancer Supplement (FACT-B) questionnaires. Inclusion criteria were: did not meet the diagnostic criteria of de novo metastatic breast cancer and patients could not cooperate QoL was assessed by FACT-BTOI variables evaluated at 6 time point. Average FACT-B TOI score was measured by the prorated aggregate score of 37 items from the FACT-B. The Wilcoxon rank sum test was used to compare the differences at each time point. The level for significance was set at p&lt;0.05.All analyses were performed with STATA 16. Results: From 2019 to 2021,a total of 86 dnMBC patients were selected and recruited in Department of breast surgery of our hospitals. Among them, 81 completed FACT-B questionnaires and their data were analyzed. Forty-one (95%) patients in the surgery group and 40 (93%) in the non-surgery group were included in the QoL analyses. A total of 362 QoL questionnaires were analyzed, 81(100%) at baseline, and 73(90%), 64(79%), 58(72%), 47(58%), 39(48%) at 6,12,18,24, and 30 months, respectively. The average FACT-B TOI scores showed no statistically significant difference between the two groups at each time point, with a P value of 0.09 at baseline, and 0.47,0.67,0.36,0.45,0.34 at 6,12,18,24, and 30 months, respectively. No significant difference was found in QOL evaluation between the two groups. Conclusions: Our prospective randomized trial showed that compared with non-surgery counterparts, locoregional surgery does not improve QoL of patients with dnMBC. Clinical trial information: 20200212.
Teclistamab in Relapsed or Refractory Multiple Myeloma
Authors: Philippe Moreau, Alfred L. Garfall, Niels W.C.J. van de Donk, Hareth Nahi, Jesús F. San-Miguel, Albert Oriol, Ajay K. Nooka, Thomas Martin, Laura Rosinol, Ajai Chari, Lionel Karlin, Lotfi Benboubker, Maria-Victoria Mateos, Nizar Bahlis, Rakesh Popat, Britta Besemer, Joaquín Martínez-López, Surbhi Sidana, Michel Delforge, Lixia Pei, Danielle Trancucci, Raluca Verona, Suzette Girgis, Shun X.W. Lin, Yunsi Olyslager, Mindy Jaffe, Clarissa Uhlar, Tara Stephenson, Rian Van Rampelbergh, Arnob Banerjee, Jenna D. Goldberg, Rachel Kobos, Amrita Krishnan, Saad Z. Usmani
Journal: New England Journal of Medicine (2022)

Teclistamab is a T-cell–redirecting bispecific antibody that targets both CD3 expressed on the surface of T cells and B-cell maturation antigen expressed on the surface of myeloma cells. In the phase 1 dose-defining portion of the study, teclistamab showed promising efficacy in patients with relapsed or refractory multiple myeloma.
The impact of detrusor wall hypertrophy and presence of overactive bladder on urine continence return in patients after radical prostatectomy due to prostate cancer
Authors: A. Ostrowski, K. Juszczak, F.R. Kowalski, M. Ostrowska, J. Wilamowski, P. Lipowski, J. Adamowicz, T.A. Drewa
Journal: European Urology (2022)
LGG-17. Preventing recurrence: targeting molecular mechanisms driving tumor growth rebound after MAPKi withdrawal in pediatric low-grade glioma
Authors: Daniela Kocher, Florian Selt, Gintvile Valinciute, Julia Zaman, David Vonhören, Stefan Pusch, Romain Guiho, Juan Pedro Martinez-Barbera, Andreas von Deimling, Stefan M Pfister, David T W Jones, Tilman Brummer, Olaf Witt, Till Milde, Romain Sigaud
Journal: Neuro-Oncology (2022)

Abstract Pediatric low-grade gliomas, a diverse group of WHO grade 1 and 2 glial or glioneural tumors, comprise the most common category of primary brain tumors in children. The majority of these tumors are driven by alterations in the MAPK pathway, making them in principle susceptible to MAPKi therapy. While patients often benefit from MAPKi during treatment, tumor rebound may occur once treatment is stopped, constituting a significant clinical challenge. BT-40, patient-derived cells with molecular features of pleomorphic xanthoastrocytoma (BRAFV600E, CDKN2Adel), were used to model the rebound growth in vitro, based on viable cell counts in response to treatment and withdrawal of the clinically relevant BRAFV600E specific inhibitor dabrafenib. Standard-of-care chemotherapy (vincristine and carboplatin) was used as a reference. MAPK pathway reactivation upon withdrawal was assessed by WB and qPCR analysis. Based on the observed cell-regrowth and MAPK-reactivation pattern, key-timepoints during withdrawal were identified, which are currently being further analyzed through RNAseq and phospho-/proteomics. BT-40 cells started to proliferate again two days after dabrafenib withdrawal, and earliest five days after chemotherapy withdrawal. MAPK pathway activity, based on Mek and Erk phosphorylation, reached baseline levels three hours after dabrafenib withdrawal, this was associated with 2.5-fold increased c-Fos gene expression two hours after withdrawal. The earlier cell regrowth after dabrafenib withdrawal compared to chemotherapy withdrawal matches clinical observations, making the model suitable to study the rebound. The observed MAPK overactivation suggests the growth rebound might not only be caused by a fast reactivation of the pathway but also by other mechanisms, e.g. accumulation of upstream activators due to loss of negative feedback or parallel pathways. To investigate this, key-timepoints during treatment withdrawal will be analyzed using a multi-omics approach. Based on these findings, possible rebound-driving mechanisms will be identified and further validated using BT-40 and additional PXA models in vitro and in vivo.
Systemic embolism in amyloid transthyretin cardiomyopathy
Authors: Silvia Vilches, Marianna Fontana, Esther Gonzalez‐Lopez, Lindsey Mitrani, Giulia Saturi, Mary Renju, Jan M. Griffin, Angelo Caponetti, Sahana Gnanasampanthan, Jeffeny De los Santos, Christian Gagliardi, Adrian Rivas, Fernando Dominguez, Simone Longhi, Claudio Rapezzi, Mathew S. Maurer, Julian Gillmore, Pablo Garcia‐Pavia
Journal: European Journal of Heart Failure (2022)

Although systemic embolism is a potential complication in transthyretin amyloid cardiomyopathy (ATTR-CM), data about its incidence and prevalence are scarce. We studied the incidence, prevalence and factors associated with embolic events in ATTR-CM. Additionally, we evaluated embolic events according to the type of oral anticoagulation (OAC) and the performance of the CHA
The <scp>SCF</scp>/<scp>KIT</scp> axis in human mast cells: Capicua acts as potent <scp>KIT</scp> repressor and <scp>ERK</scp> predominates <scp>PI3K</scp>
Authors: Kristin Franke, Marieluise Kirchner, Philipp Mertins, Torsten Zuberbier, Magda Babina
Journal: Allergy (2022)

The SCF/KIT axis regulates nearly all aspects of mast cell (MC) biology. A comprehensive view of SCF-triggered phosphorylation dynamics is lacking. The relationship between signaling modules and SCF-supported functions likewise remains ill-defined.Mast cells were isolated from human skin; upon stimulation by SCF, global phosphoproteomic changes were analyzed by LC-MS/MS and selectively validated by immunoblotting. MC survival was inspected by YoPro; BrdU incorporation served to monitor proliferation. Gene expression was quantified by RT-qPCR and cytokines by ELISA. Pharmacological inhibitors were supplemented by ERK1 and/or ERK2 knockdown. CIC translocation and degradation were studied in nuclear and cytoplasmic fractions. CIC's impact on KIT signaling and function was assessed following RNA interference.≈5400 out of ≈10,500 phosphosites experienced regulation by SCF. The MEK/ERK cascade was strongly induced surpassing STAT5 > PI3K/Akt > p38 > JNK. Comparison between MEK/ERK's and PI3K's support of basic programs (apoptosis, proliferation) revealed equipotency between modules. In functional outputs (gene expression, cytokines), ERK was the most influential kinase. OSM and LIF production was identified in skin MCs. Strikingly, SCF triggered massive phosphorylation of a protein not associated with KIT previously: CIC. Phosphorylation was followed by CIC's cytoplasmic appearance and degradation, the latter sensitive to protease but not preoteasome inhibition. Both shuttling and degradation were ERK-dependent. Conversely, CIC-siRNA facilitated KIT signaling, functional outputs, and survival.The SCF/KIT axis shows notable strength in MCs, and MEK/ERK as most prominent module. An inhibitory circuit exists between KIT and CIC. CIC stabilization in MCs may turn out as a therapeutic option to interfere with allergic and MC-driven diseases.
TBC1D15-Drp1 interaction-mediated mitochondrial homeostasis confers cardioprotection against myocardial ischemia/reperfusion injury
Authors: Shiqun Sun, Wenjun Yu, Haixia Xu, Congye Li, Rongjun Zou, Ne N Wu, Li Wang, Junbo Ge, Jun Ren, Yingmei Zhang
Journal: Metabolism (2022)
How network-based approaches can complement gene identification studies in frontotemporal dementia
Authors: Cemile Koçoğlu, Christine Van Broeckhoven, Julie van der Zee
Journal: Trends in Genetics (2022)

Frontotemporal dementia (FTD) is a primary cause of dementia encompassing a broad range of clinical phenotypes and cellular pathologies. Genetic discoveries in FTD have largely been driven by linkage studies in well-documented extended families, explaining most of the patients with a known pathogenic mutation. In the context of complex diseases, it is hypothesized that mutations with reduced penetrance or a combination of low-effect size variants with environmental factors drive disease. Furthermore, these genes are likely to be part of the interaction networks of known FTD genes, contributing to converging cellular processes. In this review, we examine gene discovery approaches in FTD and introduce network biology concepts as tools to assist gene identification studies in genetically complex disease.